Integrative genetics of behavior with high throughput technologies

行为的综合遗传学与高通量技术

基本信息

批准号：
9357186
负责人：
David Goldman
金额：
$ 331.91万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9357186
关键词：
4-aminospiroperidol African African American Alcohol dependence Alcoholism Alcohols Alleles American Indians Animal Model Animals Anterior Antipsychotic Agents Anxiety Autopsy Behavior Behavioral Behavioral Genetics Brain Brain imaging Brain-Derived Neurotrophic Factor CRH gene Cell model Cells Child Clinical Clozapine Cognition Cognitive deficits Collection Complex Corpus striatum structure Craniocerebral Trauma DISC1 gene DRD2 gene Data Set Diagnosis Diazepam Disease Dopamine Dorsal Drosophila genus Electroencephalography Emotions Endocrine Environmental Risk Factor Epigenetic Process Episodic memory Family Founder Generation GTP Cyclohydrolase Gene Cluster Genes Genetic Genetic Polymorphism Genetic Variation Genetic study Genomic approach Genomics Genotype Glutamates Goals Grant HTR2A gene Haplotypes Human Impulsive Behavior Impulsivity Investigation Knowledge Ligands Link Locomotion Massive Parallel Sequencing Mental disorders Methaqualone Minisatellite Repeats Mus Naltrexone National Institute of Drug Abuse Nature Neurobiology Neurosciences Nicotine Dependence Nonsense-Mediated Decay Outcome Pain Phenotype Placebo Effect Population Poverty Proteins RNA Rattus Risk Risk Factors Rivers Role Sampling Scanning Schizophrenia Science Sexual abuse Source Stress Study models Substance Addiction Suicide Terminator Codon Testosterone Translational Research Validation Variant Wistar Rats Withdrawal Woman addiction alcohol preferring rats alcohol response anti social base cannabinoid receptor chronic pain cognitive function comparative genomics craving deep sequencing dosage drug reward drug withdrawal exome sequencing externalizing behavior fatty acid amide hydrolase functional genomics gene discovery gene interaction genome wide association study genome-wide genome-wide analysis high risk high throughput technology imaging genetics induced pluripotent stem cell knockout gene metabotropic glutamate receptor 2 neuroimaging neuropeptide Y novel pediatric trauma preference proband problem drinker promoter receptor expression response risk variant serotonin transporter trait transcriptomics treatment response

项目摘要

Identification of functional variants is an end-game of analysis of genetically influenced diseases and starting point to understand roles of genes in behavioral diseases. Addictions are moderately to highly heritable but most of the genetic variance is unexplained by functional loci or replicated linkages. Using genomic approaches and by focused studies on implicated genes, we have discovered several functional loci with roles in complex behaviors relevant to alcoholism and addictions. These studies make use of founder populations, people at risk because of exposures, and model organisms. We use addiction-relevant intermediate phenotypes that are closer to gene action. Model organisms, including artificially selected mice, rats and fruitflies are used for gene discovery, as well as validation and we use cellular models including iPSC's to bridge between animal models and human. An OPRM1 Asn40Asp missense variant we found (Bergen et al, 1997) was shown by others to be functional and linked to naltrexone treatment response (Anton et al, 2008). A common, functional SNP in the serotonin transporter HTTLPR (Hu et al, 2007) enhanced linkage to OCD,neuroimaging responses to emotion, and gene x stress interactions leading to suicidality (Roy et al, 2007. Common HTR2C Ser23Cys (Lappalainen et al, 1999, Okada et al, 2004) and HTR2A Asn452His variants(Ozaki et al, 1997) were found and shown to be functional, and later linked to behavior, including clozapine response. In first-episode schizophrenics, we found that a functional DRD2 promoter polymorphism influences antipsychotic response (Lencz et al, 2006). We traced linkages of functional loci and haplotypes of NPY (Zhu et al, 2008), GCH1 (Tegeder et al, 2006) and DISC1 (Hodgkinson et al, 2004) to emotionality, schizophrenia and clinical pain outcome. By deep sequencing we found an HTR2B stop codon that is relatively common in Finns, a founder population, absent in others, and associated with but not determinant for impulsive behavior. This stop codon also cosegregated with ASPD and AUD in families and the mouse gene knockout was impulsive and high in novelty seeking and novelty induced locomotion. It leads to variable nonsense mediated decay of the HTR2B RNA and blocked HT2B receptor expression (Bevilacqua et al, Nature, 2010). A low expression Neuropeptide Y (NPY) haplotype increased anxiety and emotionality but had stronger effects on molecules (NPY RNA and protein) and intermediate phenotypes (brain imaging responses to emotion and pain/stress)(Zhou et al, Nature, 2008). Because intermediate phenotypes augment analysis of behavior (Ducci and Goldman)we proposed a multidimensional Addictions Neuroclinical Assessment based on the addiction cycle (Kwako et al, Biol Psych, 2016). The imaging genetics paradigm we helped initiate (Heinz et al, 2000; Hariri et al, 2002; Egan et al, 2001; 2003; Zubieta et al, 2003) led to groundbreaking findings. We found a mechanism of CHRNA5 Asn398, a functional locus altering nicotine addiction risk. The risk allele weakens brain connectivities including a Dorsal Anterior Cingulate/Ventral Striatal circuit predictive of craving (Hong et al, 2010). Clinical subphenotyping enabled linkage of HTR1B to antisocial alcoholism (Lappalainen et al, 1998), serotonin transporter (SLCA4) to anxiety (Mazzanti et al; Hariri et al), BDNF Val66Met to episodic memory (Egan et al, cell, 2003), and GTP cyclohydrolase to chronic pain and experimental pain response (Tegeder et al, 2006). Frontal cognitive deficit is a risk factor in schizophrenia, alcoholism and other diseases. Dopamine generally enhances prefrontal cortical efficiency. Met158, a common COMT variant, leads to four-fold reduction in COMT activity. It is thus a candidate allele for cognitive function via effect on frontal dopamine. We found an allele-dosage relationship of Met158 to frontal cognitive function and diminished cortical efficiency (Egan et al, 2001). The effect on cognition is seen in populations differing in baseline cognitive function: schizophrenia, head injury (Lipsky et al, 2005, 2011), & controls (Malhotra et al, 2002, 2009). We proposed that Val158 has a counter-advantage: stress resiliency. In two populations Met158 predicted anxiety in women and decreased frontal EEG coherence (Enoch et al, 2003), and Met158 was associated with lower resiliency to pain/stress (Zubieta et al, Science, 2003; Diatchenko et al, 2005, 2006. We have extended knowledge of GxE effects of stress related genes such as COMT, NPY, SLC6A4 and SLC6A4 in many studies using both behavioral and endocrine outcomes (Lovallo et al 2015, 2016). A functional polymorphism of Fatty Acid Amide Hydrolase (FAAH) which metabolizes the endogenous ligand for cannabinoid receptors, specifically predicts placebo response to pain (Pecina et al, 2014). GWAS, transcriptomics and exome sequencing are global approaches that enable genomic spaces to be searched independent of prior hypotheses. The Chr 4 GABAA subunit cluster was implicated in alcoholism by family linkage (Long et al, 1998), an effect that appears anxiety-modulated (Enoch et al, 2006). Another GABAA gene cluster implicated in alcoholism and alcohol response is located on Chr 5 (Radel et al, 2005). GABRA6 has a missense variant associated with alcohol dependence and response to alcohol and diazepam (Iwata et al, 2005). A family linkage scan yielded genome-wide significant linkage of CRH-BP to an alcoholism-associated EEG trait and this was supported by association in two populations (Enoch et al, 2008). GWAS of EEG (Hodgkinson et al, PNAS, 2010) in Plains Indians detected three independent genome-wide significant loci(Hodgkinson et al, PNAS 2010). Via GWAS, a schizophrenia risk locus was identified in multiple populations (Lencz et al, Nat Commun, 2013). Founder, phenotypically extreme, and exposed populations enhance power to detect gene effects. Our Finnish dataset, derived from a founder population, was ascertained via criminal alcoholic probands. SW and Plains Indian samples represent founder populations. An African American substance dependence sample with high adversity revealed GxE of childhood trauma and HTTLPR in suicidality (Roy et al, 2007). Stress and poverty, but not African ancestry, predicted high risk of addictions (Ducci et al, 2009). An MAOA VNTR previously linked to dyscontrol via stress interaction was linked to outcomes of alcohol dependence and ASPD in American Indian women, of whom half had been sexually abused as children (Ducci et al, 2008). A strong interaction between a MAOA VNTR and testosterone was observed in the Finnish criminal sample (Sjoberg et al, 2008). As mentioned, deep sequencing in Finns detected a population-specific HTR2B Stop codon significant for impulsivity (Bevilacqua et al, Nature, 2010). We exome-sequenced an artificially selected animal model for alcoholism, the P/NP rat, and discovered a stop codon in the metabotropic glutamate receptor 2 (Grm2) gene that leads to altered glutamate function and increased alcohol preference in alcohol-preferring rats (Zhou et al, 2013). The Grm2 Stop codon is common (0.08) in parental Charles River Wistar rats, and fixed in Wistar from some sources. It leads to uncompensated changes in glutamate function. It was genetically fixed by artificial selection in the alcohol preferring and non-preferring rats illustrating the power of using such strains to discover alleles that alter behavior. Via parallel exome sequencing in selected strains and people we are identifying genes involved in drug reward and withdrawal As facilitated by a NIDA RFA leading to two U01 grants we have identified new loci altering addiction in rat and Drosophila.

功能变体的识别是分析受遗传影响的疾病的分析和了解基因在行为疾病中的作用的起点。成瘾是适度的，但大多数遗传差异无法通过功能基因座或复制的联系来解释。使用基因组方法并通过对牵连基因的重点研究，我们发现了几个功能基因座，在与酒精中毒和成瘾有关的复杂行为中作用。这些研究利用基础人群，由于暴露而面临风险的人和模型生物。我们使用与基因作用更接近的与成瘾相关的中间表型。模型生物，包括人为选择的小鼠，大鼠和果蝇用于基因发现以及验证，我们使用包括IPSC在内的细胞模型在动物模型和人之间桥接。我们发现的OPRM1 ASN40ASP错义变体（Bergen等，1997）被其他人具有功能性，并与纳曲酮治疗反应相关（Anton等，2008）。 5-羟色胺转运蛋白HTTLPR（Hu等，2007）中常见的功能性SNP增强了与OCD的联系，对情绪的神经成像反应以及Gene X压力相互作用，导致自杀（Roy等，2007。CommonHtr2c Ser23cys）（Lappalainen等人（Lappalainen等人）发现变体（Ozaki等，1997），并显示出与行为相关的，包括氯氮平的响应，我们发现功能性的DRD2启动子多态性会影响抗精神病性反应（Lencz et and tripialitial Locipy，Z）。（Tegeder等，2006年）和DISC1（Hodgkinson等，2004），通过深度测序，我们发现了一个相对常见的HTR2B终止密码子，在其他人中，与其他人相关的是，我们发现了一个相对常见的HTR2B终止密码子。冲动和高新颖的寻求和新颖性引起的运动。它导致HTR2B RNA的无义介导的衰减变化并阻塞HT2B受体表达（Bevilacqua等，Nature，2010年）。低表达神经肽Y（NPY）单倍型增加了焦虑和情绪性，但对分子（NPY RNA和蛋白质）和中间表型（脑成像对情绪和疼痛/压力的反应）的影响更强（Zhou等人，自然，2008年）。由于中间表型增强行为分析（DUCCI和高盛），我们提出了基于成瘾周期的多维成瘾神经临床评估（Kwako等，Biol Psych，2016）。我们帮助启动的成像遗传学范式（Heinz等，2000; Hariri等，2002; Egan等，2001; 2003; Zubieta et al，2003）导致了突破性的发现。我们发现了CHRNA5 ASN398的机制，这是一个改变尼古丁成瘾风险的功能基因座。风险等位基因削弱了大脑连接性，包括渴望的背扣带回/腹侧纹状体回路（Hong等，2010）。临床亚典型分型启用HTR1B与反社会酒精中毒的联系（Lappalainen等，1998），5-羟色胺转运蛋白转运蛋白（SLCA4）与焦虑（Mazzanti等； Hariri等），BDNF val66ment，Met 2006）。额叶认知缺陷是精神分裂症，酒精中毒和其他疾病的危险因素。多巴胺通常提高额叶皮质效率。 MET158是一种常见的COMT变体，可导致COMT活动减少四倍。因此，它是通过对额叶多巴胺的作用来实现认知功能的候选等位基因。我们发现Met158与额叶认知功能和皮质效率降低的等位基因剂量关系（Egan等，2001）。在基线认知功能不同的人群中，人们可以看到对认知的影响：精神分裂症，头部损伤（Lipsky等，2005，2011）和对照组（Malhotra等，2002，2009）。我们提出Val158具有相反的优势：应力弹性。在两个人群中，MET158预测女性的焦虑和额叶的相干性降低（Enoch等，2003），Met158与对疼痛/压力的弹性降低有关（Zubieta等，Science，2003; Diatchenko等，2005,2005，2006。和内分泌结果（Lovallo等，2015年，2016年）。 GWAS，转录组学和外显子组测序是使基因组空间可以独立于先前的假设进行搜索的全局方法。 CHR 4 GABAA亚基簇与家庭连接有关（Long等，1998）与酒精中毒有关，这种作用似乎是焦虑调节的（Enoch等，2006）。涉及酒精中毒和酒精反应的另一个GABAA基因簇位于Chr 5（Radel等，2005）上。 Gabra6具有与酒精依赖以及对酒精和地西epam的反应有关的错义变体（Iwata等，2005）。家庭连锁扫描产生了CRH-BP与酒精中毒相关的脑电图的显着连锁，这得到了两个人群的关联支持（Enoch等，2008）。脑电图的GWA（Hodgkinson等，PNA，2010年）在平原印第安人发现了三个独立的全基因组显着基因座（Hodgkinson等，PNAS，2010年）。通过GWAS，在多个人群中发现了精神分裂症的风险基因座（Lencz等，Nat Commun，2013年）。创始人，表型极端和暴露的种群增强了检测基因效应的能力。我们的芬兰数据集是从创始人人群中得出的，是通过犯罪酒精饮料来确定的。 SW和Plains印度样品代表创始人人群。具有高逆境的非裔美国物质依赖性样本揭示了自杀性的儿童创伤和HTTLPR的GXE（Roy等，2007）。压力和贫穷，但不是非洲血统，预测了成瘾的高风险（Ducci等，2009）。以前通过压力相互作用与Dyscontrol相关的MAOA VNTR与美洲印第安妇女的酒精依赖和ASPD的结果有关，其中一半是儿童性虐待的（Ducci等，2008）。在芬兰的犯罪样本中观察到了MAOA VNTR和睾丸激素之间的强烈相互作用（Sjoberg等，2008）。如前所述，芬兰人中的深层测序检测到了人群特异性的HTR2B停止密码子对冲动性的重要意义（Bevilacqua等，Nature，2010年）。我们对酒精中毒，P/NP大鼠进行了人工选择的动物模型，并在代谢型谷氨酸受体2（GRM2）基因中发现了一个终止密码子，从而导致谷氨酸功能改变，并在酒精挑选的大鼠中增加酒精偏好（Zhou等，2013）。 GRM2停止密码子在父母Charles River Wistar大鼠中很常见（0.08），并从某些来源固定在Wistar中。它导致谷氨酸功能无偿变化。它是通过人工选择在酒精偏爱和非偏爱大鼠中的人工选择上固定的，这些大鼠说明了使用这种菌株发现改变行为的等位基因的力量。通过选定菌株和人员的平行外显子组测序，我们正在确定与药物奖励和戒断有关的基因，这是由NIDA RFA促进的，导致了两种U01赠款，我们已经确定了大鼠和果蝇中的成瘾的新基因座。